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S2 Case 3 - asthma & COPD > Physiochemical Properties > Flashcards

Physiochemical Properties Flashcards

1
Q

What must an “ideal” oral drug be?

A

Dissolve
Survive in 1.5-8.0 pH range
Survive intestinal bacteria
Cross membranes
Survive liver metabolism
Avoid active transport to bile
Avoid excretion by kidneys
Partition into target organ
Avoid partition to undesired places

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2
Q

What is a physiochemical property?

A

A parameter that can be derived from physical + chemical characteristics of a molecule

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3
Q

What are the physiochemical properties?

A

Solubility
Stability
Solid-state properties
Partition coefficient
Ionisation constant

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4
Q

What is Lipinski’s rule of 5?

A

No more than 5 H bonds
No more than 10 H bond donors
Mr <500
LogP <5

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5
Q

What is lipophilicity?

A

Ability of chemical compound to dissolve in fats, oils, lipids + non-polar solvents

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6
Q

What does lipophilicity determine?

A

ADMET

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7
Q

What does it mean if logP is high?

A

High lipophilicity

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8
Q

How do you determine logP using shake flask method?

A

Look at distribution between octanol + H2O
Analyse drug conc by UV

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9
Q

How do you determine logP using chromatography?

A

Microtiter plate format
Compound detection by MS
Retention time linked to partition coefficient
Limited by compound properties - eg. purity

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10
Q

What is clogP?

A

Calculated logP

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11
Q

What happens to binding as logP increases?

A

Increases

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12
Q

What happens to aqueous solubility as logP increases?

A

Decreases

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13
Q

What happens to absorption through membrane as logP increases?

A

Increases

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14
Q

What is the substituent hydrophobicity constant?

A

Measure of substituent’s hydrophobicity relative to H

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15
Q

What does positive values of the substituent hydrophobicity constant indicate?

A

More hydrophobic (lipophilic) than H

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16
Q

What does negative values of the substituent hydrophobicity constant indicate?

A

Less hydrophobic than H

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17
Q

How is it possible to calculate logP (clogP) from substituent hydrophobicity constant?

A

LogP + value + value

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18
Q

What do you use when comparing neutral molecules?

A

logP

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19
Q

What do you use when comparing mixed neutral + charged molecules?

A

logP

20
Q

What do you use when comparing all charged molecules?

A

logD

21
Q

What happens to logD in acidic drugs when pKa increases?

A

More ionised = logD decreases

22
Q

What happens to logD in basic drugs when pKa increases?

A

LogD increases

23
Q

Describe fluorine

A

Small atom
High electronegativity

24
Q

What does covalently bound fluorine do?

A

Occupy vol smaller than methyl, amino or hydroxyl groups
BUT larger than H atom

25
Q

When you add F to an acid what happens?
CH3COOH —-> CH2FCOOH

A

pKa decreases = increased acidity

26
Q

What happens to lipophilicity if you substitute H for F?

A

Increases lipophilicity slightly

27
Q

What happens to logD if you substitute H for F?

A

Decreases

28
Q

What are the ways of investigating molecular size?

A

e- density
Molecular weight
Polar surface area
Van der Waals
Molar refractivity

29
Q

What is the Hammett substituent constant?

A

A measure of electron-withdrawing or electron-donating influence of substituents

30
Q

How can the Hammett substituent constant be measured?

A

Experimentally or tabulated

31
Q

What will electron-withdrawing groups have?
Hammett substituent constant

A

Positive value

32
Q

What will electron-donating groups have?
Hammett substituent constant

A

Negative value

33
Q

What happens in electron-withdrawing groups?
Hammett substituent constant

A

Charge stabilised by X
Eqm shifts right
Kx > KH

34
Q

What happens in electron-donating groups?
Hammett substituent constant

A

Charge destabilised
Eqm shifts left
Kx < KH

35
Q

What are the 2 types of substitution?

A

Meta
Para

36
Q

What is meta due to?

A

Inductive effect

37
Q

What is para due to?

A

Inductive + resonance effects

38
Q

Describe aliphatic electronic effects

A

Purely inductive effects
Hydrolysis rates measured under basic + acidic conditions
Defined by σI

39
Q

If X is electron donating what will happen to hydrolysis rate of aliphatic electronic effects?

A

Decreases

40
Q

If X is electron withdrawing what will happen to hydrolysis rate of aliphatic electronic effects?

A

Increases

41
Q

What is molecular polar SA?

A

Surface sum of all polar atoms present in the molecule
Usually N, O + their attached H

42
Q

How is molecular polar SA calculated?

A

From surface/space filling models

43
Q

How do rotatable bonds effect?

A

Increased flexibility reduces oral bioavailability = <10

44
Q

How do H bond donors + acceptors effect?

A

Polarity reduces permeability
Lipinski’s rule

45
Q

How do aromatic rings effect?

A

Effect solubility

46
Q

How does pKa effect?

A

Drug needs to be ionised
pKa needs to be relevant to logD + target binding site

47
Q

What does it mean if there is a high logS value?

A

Good solubility

S2 Case 3 - asthma & COPD (25 decks)

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